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Emerging concepts in pain management

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Emerging concepts in Pain Management

Emerging concepts in Pain Management

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  • 9402 Final Show 2 Nov 21, 2012 DRAFT Arachidonic acid is a polyunsaturated fatty acid , one of the essential fatty acids required by most mammals. It is present in the membranes of the body's cells , and is a precursor in the production of eicosanoids : the prostaglandins , thromboxanes , prostacyclin and the leukotrienes . A prostaglandin is any member of a group of lipid compounds that are derived from fatty acids and have important functions in the animal body. They are mediators and have a variety of strong physiological effects; although they are technically hormones they are rarely classified as such. There are two pathways for metabolism of arachidonic acid to prostaglandins, mediated by COX-1 and COX-2. COX-1 is constitutive and is responsible for the production of prostaglandins that protect the GI tract and maintain normal platelet function. COX-2 controls the production of prostaglandins that mediate inflammation and pain. 1,2 NSAIDs inhibit both COX-1 and COX-2 and are non-specific in their mode of action, controlling pain and inflammation but also causing characteristic adverse effects. 3 New strategies have focused on the development of therapeutic agents with pharmacological activity based on specific inhibition of COX-2. 3 The rationale is that the therapeutic effects of NSAIDs are achieved by COX-2 inhibition, but that many of the toxic effects, most commonly gastroduodenal injury, result from COX-1 inhibition. 4 COX-2 is also found as a normal constituent of certain tissues such as the brain, kidney and reproductive tract. 1 --------------------------------------------------------------------------------- Cyclooxygenase in Platelets COX 1 is the only isoform of COX present in platelets and is responsible for the synthesis of thromboxane A2 (TxA2) which in turn is responsible for promoting platelet aggregation. Non-specific COX inhibitors such as ASA and NSAIDs inhibit the production of TxA2 via their effect on COX 1 resulting in a decrease in platelet aggregation and a mild bleeding diathesis. Since celecoxib, a cyclooxygenase-2 specific inhibitor, has no inhibitory effect on COX 1 at doses associated with anti-inflammatory and analgesic activity it should have no effect on platelet function. NB : There is not a linear correlation between reduction of thromboxane levels and inhibition of platelet aggregation and bleeding time. Almost complete inhibition of thromboxane is required before changes in aggregation and bleeding time occur. This happens with therapeutic doses of NSAIDs but only ~50% inhibition of TXB2 occurs with doses of celecoxib 3-4 x the maximum therapeutic dose. Cyclooxygenases Prostaglandins are produced from arachidonic acid by cyclooxygenases ( COX-1 and COX-2 ). COX-1 is responsible for the baseline levels of prostaglandins while COX-2 produces prostaglandins through stimulation. While COX-1 is located in the blood vessels , stomach and the kidneys , prostaglandin level are induced by COX-2 in scenarios of inflammation . The recent development of COX-2 inhibitors, known as coxibs , allow the circumvention of the negative gastrointestinal effects while effectively reducing inflammation. [ edit ] Function There are currently nine known receptors of prostaglandins on various cell types. Prostaglandins thus act on a variety of cells such as vascular smooth muscle cells causing constriction or dilation, on platelets causing aggregation or disaggregation and on spinal neurons causing pain. Prostaglandins act principally on a subfamily of G protein coupled receptors . Most of these GPCRs are located at the periphery of target cells at the plasma membrane , however, a few exist within the cell at the nuclear envelope . They may also act upon peroxisome proliferator-activated receptors . Prostaglandins have a wide variety of actions but most cause muscular constriction and mediate inflammation. Other effects include calcium movement, hormone regulation and cell growth control. Thromboxane is created in platelets and causes vascular constriction and platelet aggregation. Prostacyclin comes from cells in the blood vessel walls and is antagonistic to thromboxane
  • Arachidonic acid is a polyunsaturated fatty acid , one of the essential fatty acids required by most mammals. It is present in the membranes of the body's cells , and is a precursor in the production of eicosanoids : the prostaglandins , thromboxanes , prostacyclin and the leukotrienes . A prostaglandin is any member of a group of lipid compounds that are derived from fatty acids and have important functions in the animal body. They are mediators and have a variety of strong physiological effects; although they are technically hormones they are rarely classified as such. There are two pathways for metabolism of arachidonic acid to prostaglandins, mediated by COX-1 and COX-2. COX-1 is constitutive and is responsible for the production of prostaglandins that protect the GI tract and maintain normal platelet function. COX-2 controls the production of prostaglandins that mediate inflammation and pain. 1,2 NSAIDs inhibit both COX-1 and COX-2 and are non-specific in their mode of action, controlling pain and inflammation but also causing characteristic adverse effects. 3 New strategies have focused on the development of therapeutic agents with pharmacological activity based on specific inhibition of COX-2. 3 The rationale is that the therapeutic effects of NSAIDs are achieved by COX-2 inhibition, but that many of the toxic effects, most commonly gastroduodenal injury, result from COX-1 inhibition. 4 COX-2 is also found as a normal constituent of certain tissues such as the brain, kidney and reproductive tract. 1 --------------------------------------------------------------------------------- Cyclooxygenase in Platelets COX 1 is the only isoform of COX present in platelets and is responsible for the synthesis of thromboxane A2 (TxA2) which in turn is responsible for promoting platelet aggregation. Non-specific COX inhibitors such as ASA and NSAIDs inhibit the production of TxA2 via their effect on COX 1 resulting in a decrease in platelet aggregation and a mild bleeding diathesis. Since celecoxib, a cyclooxygenase-2 specific inhibitor, has no inhibitory effect on COX 1 at doses associated with anti-inflammatory and analgesic activity it should have no effect on platelet function. NB : There is not a linear correlation between reduction of thromboxane levels and inhibition of platelet aggregation and bleeding time. Almost complete inhibition of thromboxane is required before changes in aggregation and bleeding time occur. This happens with therapeutic doses of NSAIDs but only ~50% inhibition of TXB2 occurs with doses of celecoxib 3-4 x the maximum therapeutic dose. Cyclooxygenases Prostaglandins are produced from arachidonic acid by cyclooxygenases ( COX-1 and COX-2 ). COX-1 is responsible for the baseline levels of prostaglandins while COX-2 produces prostaglandins through stimulation. While COX-1 is located in the blood vessels , stomach and the kidneys , prostaglandin level are induced by COX-2 in scenarios of inflammation . The recent development of COX-2 inhibitors, known as coxibs , allow the circumvention of the negative gastrointestinal effects while effectively reducing inflammation. [edit] Function There are currently nine known receptors of prostaglandins on various cell types. Prostaglandins thus act on a variety of cells such as vascular smooth muscle cells causing constriction or dilation, on platelets causing aggregation or disaggregation and on spinal neurons causing pain. Prostaglandins act principally on a subfamily of G protein coupled receptors. Most of these GPCRs are located at the periphery of target cells at the plasma membrane, however, a few exist within the cell at the nuclear envelope. They may also act upon peroxisome proliferator-activated receptors. Prostaglandins have a wide variety of actions but most cause muscular constriction and mediate inflammation. Other effects include calcium movement, hormone regulation and cell growth control. Thromboxane is created in platelets and causes vascular constriction and platelet aggregation. Prostacyclin comes from cells in the blood vessel walls and is antagonistic to thromboxane

Emerging concepts in pain management Emerging concepts in pain management Presentation Transcript

  • EMERGING PHARMACOLOGICAL &NONPHARMACOLOGICAL ASPECTS IN PAIN MANAGEMENTDr. Muralidhar JoshiDirector, Pain Management Centre,Kamineni Hospitals, King Koti,Hyderabad
  • PAIN• Greek goddess – ‘POINE’ Pain• It is defined as ‘’ Unpleasant sensory & emotional experience associated with actual or potential damage or described in terms of such damage” – IASP 1974• In simple words, patient says ‘it hurts’• Why are we discussing this topic ?• What is the relevance to today’s session ?
  • Epidemiology• World over 22% patients in chronic pain• Economic impact unimaginable• India – 35 Crores (1947), 117 Crores (2010)• Survival rate 32-35 yrs (1947), 47yrs (1990), 67 yrs (2010)• Diabetic population 25 % by 2020• Age related degenerative disorders• ‘Empty Nest Syndrome’
  • TYPES OF PAIN• SUPERFICIAL/CUTANEOUS PAIN• DEEP NON-VISCERAL PAIN• VISCERAL PAIN• REFERRED PAIN• NEUROPATHIC PAIN• PSYCHOGENIC/FUNCTIONAL PAIN
  • TYPES OF PAIN1. ACUTE PAIN It is related in time & the severity is proportional to the healing of an injury or disease. As healing progresses pain decreases.2. CHRONIC PAIN The same pain will be termed as chronic and the pain persists beyond the normal healing period for that particular injury or disease. It could be because of recurrent injury or by an unexplained mechanism
  • Can Acute Pain Evolve Into Chronic Pain? (The Theory)• Extensive and Persistent cascade of neurochemical mediators triggered by tissue injury• Stimulate A beta fibers which connect in the Rexed lamina of the spinal cord to sprout, grow and connect to A delta fibers• This then may progress to long-term, permanent, neurological change that can lead to Sensitisation, Allodynia, HyperalgesiaCanadian Consortium on Pain Mechanisms, Diagnosis and Management-2004
  • Sensitisation 10 Hyperalgesia 8 Normal pain responsePain intensity 6 Injury 4 Allodynia 2 0 Stimulus intensity Gottschalk A, et al. Am Fam Physician. 2001;1979-1984.
  • WHY CHRONIC PAIN SHOULD BE TREATED ?• Vocational, social, family dysfunction• Extensive, costly, nonproductive inv. & tr.• Mental & Physical suffering• ↑ Disability costs, ↑health care costs• ↓ Immune response• Death often by suicides• Distorted Analysis
  • WORLD IS TRAVELLING FROM INVASIVE OPTIONS TO NONINVASIVE WAYS OF HANDLING THE SITUATION
  • Receptors at Skin level • Touch • Temperature • Tactile sensation • Light pressure • Deep pressure • Free nerve endings • Unknown receptors???
  • PATHOPHYSIOLOGY
  • f-MRI (Phantom limb pain)
  • Recent Developments• Move from empirical therapies to a mechanism based approach• Newer drugs targeting specific receptor subtypes• Evidence Based Medicine• International Guidelines, Cochrane Review• Multidisciplinary approach Anita Holdcroft, Ian Power. Clinical Review – Recent Developments of management of pain. In BMJ 2003; 326; 635.
  • “Real People & Real Pain” What are the Emerging Pharmacological &Nonpharmacological Aspects in Pain Management ?
  • Emerging Pharmacological Aspects• Local applicants• Role of paracetamol• Role of NSAID’s ; Cox-2 Inhibitors• Role of Opioids• Option of Multimodal Analgesia• Options for Neuropathic Pain• Future prospects
  • SUPERFICIAL/CUTANEOUS PAIN• Rubefacients (salicylates & nicotinamides ) offer lesser pain relief than NSAID’s topical application – 2009• Topical NSAID’s provide good pain relief with lesser side effects than oral NSAID’s - 2010• Capsaicin local application for neuropathic pain may be of help if other therapies donot work – May 2009
  • COX Pathway and NSAIDs, COX-2 Glucocorticoids Arachidonic acid (-) (block mRNA expression) (an fatty acid) (-) (-) COX-1 NSAIDs COX-2 Coxibs Normal Normal Inducible constituent constituent gastric cytoprotection  inflammation  brain renal sodium / water balance  kidney  pain platelet aggregation  ovary  fever  uterus And Cardiac Impact
  • NSAID’s, Cox-2• Does Cox-2 Inhibitors Still Have a Role ?• Celecoxib (Celebrix) currently used (30 times stronger inhibition of Cox-2 over Cox-1)• Rofecoxib (Vioxx) & Valdeicoxib(Bextra) 2004; Risk of Myocardial Infarction & CVA (300 times stronger inhibition of Cox-2) Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C (June 2006). "Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk o . BMJ 332 (7553): 1302–8. doi:10.1136/bmj.332.7553.1302. PMID 16740558 (138 trials, 1,50,000 patients)
  • NSAID’s, Cox-2• Cox 2 Inhibitors Use – Colo-rectal polyps, Menstrual cramps, RA, Psoriatic arthritis, Sports Injuries, Neuroblastomas, cancers• Side effects – Insomnia, diarrhoea, pain abdomen, nausea, ulcers, perforations (lesser extent ?). Risk of MI, CVA Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C (June 2006). "Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk o . BMJ 332 (7553): 1302–8. doi:10.1136/bmj.332.7553.1302. PMID 16740558 (138 trials, 1,50,000 patients)
  • Multimodal Analgesia• Opportunities to intervene and diminish pain exist in multiple points along the pain pathway• It is synergistic to use combination drugs to target multiple points of pain pathway for pain control• In effect – reduced doses of each analgesic, improved pain control with synergistic approach, reduced side effects Raffa RB. J Clin Pharm Ther 2001;26:257
  • Tramadol (Tapentadol) + Paracetamol• Tramadol – binds to μ receptors & also inhibits uptake of serotonin& norepinephrine• Tapentadol – μ receptors & norepinephrine uptake inhibition• Paracetamol – inhibits nitric oxide• Both in effect inhibit release of substance P and hence pain relief Paul et al. Analgesic efficacy & safety of Tramadol/acetaminophen combination in treatment of CLBP; a multicenter outpatient, randomised, double blind, placebo controlled trial. The Journal of Rheumatology 2004; 31; 2454-63
  • DEEP NON-VISCERAL PAIN• Paracetamol offers better Pain Relief than Placebo in OA – 2009• Early ambulation helpful in LBA, however patients with sciatica have no or little benefit from bed rest – 2010• Muscle relaxants are helpful non-specific back pain• NSAID’s provide pain relief in acute & chronic low back pain for short term - 2011
  • DEEP NON-VISCERAL PAIN• Glucosamine (Rotta Brand) was superior to Placebo - 2009• Opioids in long-term chronic pain is still debatable – 2010• Local corticosteroid injection provides short term relief in Carpal Tunnel Syndrome – 2009• IA steroid offers rapid and short term relief in OA knee when compared to IH which has slower and sustained effect - 2009
  • NEUROPATHIC PAIN• Antidepressants for neuropathic pain; effective in 1 in 3 – 2010• Systemic administration of Lidocaine neuropathic pain better than placebo - 2009• Gabapentin effective in chronic pain but inconclusive in acute pain – 2010• Pregabalin effective in Neuropathic Pain & Fibromyalgia but not acute pain - 2010
  • NEUROPATHIC PAIN• Tramadol is effective in neuropathic pain – 2009• Lamotrigine seems to be ineffective in neuropathic pain – 2011• Topical Lidocaine for PHN – Not a first line treatment – July 2008
  • Interventional Pain ManagementIt is the discipline of medicine devoted to thediagnosis and treatment of pain relateddisorders principally with the application ofinterventional techniques in managing subacute, chronic, persistent and intractable pain,independently or in conjunction with othermodalities of treatment
  • What are those techniques?• Non imaging assisted interventions• Fluoroscopy assisted interventions• USG Assisted interventions• CT guided interventions• Advanced pain management therapies• Invasive neurosurgical techniques
  • Non Imaging Assisted Interventions
  • Trigger Point InjectionInterlaminar Epidural Injection
  • FluoroscopyAssisted Procedures
  • Trigeminal RFA
  • Interlaminar Epidural Injection
  • Transforaminal Epidural
  • Epiduroscopy
  • CT GuidedProcedures
  • CT Guided Lumbar Sympathetic Block
  • Radiofrequency Generator
  • Radiofrequency Ablation
  • Intradiscal Therapies
  • Spinal Cord Stimulation• Dorsal column stimulation• Time tested• Expensive• No structural damage• Substituting pain with pleasant sensation
  • Intrathecal Drug Delivery System
  • Advanced Neurosurgical Interventions• Vertebroplasty & Kyphoplasty• Percutaneous cordotomy• Deep brain stimulation• Tractotomy• Thalamotomy
  • Benefits of IPM Procedures• Non-analgesic benefits – limitation of side effects, improved QOL, weight gain• Less sedated, alert and satisfied patients• Combination of medications and interventions• Meaningful expectation• Imaging assistance offers safety & accuracy
  • Some other Issues• Meralgia Paresthetica – RCT Required• Vitamin B – Variable• Trigeminal Neuralgia – Nonanticonvulsants• Vertebroplasty – JAMA• Disc problems – surgeries• Injection therapies for back
  • CONCLUSIONS• Pain is the one of the most common reasons that people seek medical attention, it needs to be managed aggressively and systematically• Treat acute pain promptly & aggressively to possibly avoid chronic pain• Synergy: use combination drugs to target multiple points of pain pathway• Multi-modal management of pain can provide better efficacy with reduced side effects